Emphysema, a major component of chronic obstructive pulmonary disease (COPD), is marked by the irreversible destruction of lung tissue and compromised gas exchange in affected individuals. The chronic inflammatory mechanisms that give rise to and perpetuate the observed pathophysiology of emphysema include the recruitment and activation of leukocytes as well as the establishment of an imbalance between leukocytic proteases and their endogenous inhibitors. The dysregulation of these processes ultimately leads to a loss in lung homeostasis and increased epithelial damage and cell death. However, the role that the lung epithelium plays in sustaining the activation of resident and infiltrating leukocytes and their associated proteases during the development of emphysema is unclear. An increasing number of studies have implicated the epithelial-derived alarmin and IL-1 family member IL-33, which signals via the ST2 receptor, as being an important mediator of pulmonary inflammation in a variety of contexts. Recent work has described the formation of highly active IL-33 forms generated by leukocytic protease cleavage in the extracellular milieu during acute lung injury. Moreover, elevated IL-33 production from epithelial progenitor cells has been observed in human COPD tissues. Based on these findings and preliminary data that we have generated in ST2 knockout mice using an experimental model of elastase-induced emphysema, we hypothesize that the IL- 33/ST2 axis is a critical regulator of inflammation associated with the progression of emphysema, and therefore may serve as a novel therapeutic target in the treatment of COPD. In order to test this hypothesis and elucidate the mechanism by which IL-33/ST2 signaling may promote the progression of emphysema, we will define the cellular and molecular immune profile of ST2-deficient mice following airway elastase challenge. In addition, we will assess the role of macrophage- and neutrophil-derived proteases in regulating the production of highly active IL-33 forms during emphysema. Furthermore, we will establish whether highly active IL-33 forms are associated with human COPD tissues, and evaluate the efficacy of ST2 blockade to inhibit the progression of experimental emphysema. These proposed studies have the potential to uncover a significant, but so far unappreciated, driver of emphysema as well as identify a novel therapeutic target for the treatment of COPD. This work will be supplemented by a rigorous training plan guided by a diverse and experienced mentoring team with expertise in lung physiology, immunology, pathology, and clinical pulmonology. The training aspects of this proposal will promote scientific independence and integrity in the context of lung disease by honing laboratory, classroom, presentation, and writing skills.